The thyroid gland is situated in the neck region and
consists of two lateral lobes, one on each side of the trachea
immediately below the larynx. Three hormones are produced and
released into the blood, Tri-iodothyronine(T3), Thyroxine(T4),
Calcitonin(CT). The T3 and T4 increase metabolic rate in most
cells by stimulating oxidative process. Hormones are essential
for normal physical growth, sexual maturation and mental
development. Production and release of thyroid hormones are
controlled by thyroid stimulating hormone (TSH) secreted by
anterior pituitary.

The disturbances of thyroid function have diverse effects on
male and female infertility. The chance of thyroid disease is
5-10 more in female than in male. As Thyroid dysfunction is
known to reduce the likelihood of pregnancy and to adversely
affect pregnancy outcome, estimation of thyroid function is an
integral part of infertility works-up.

Both hypo-and hyperthyroidism can be readily treated and, if
missed, is associated with an increased risk of miscarriage and
possible long-term health consequences for the child.1 The
difficulty is in identifying the sub-clinical hypothyroidism and
treating it appropriately as it too can adversely affect
ovulation and cause recurrent pregnancy loss as well.

HYPOTHYROIDISM AND INFERTILITY

Prevalence of hypothyroidism in the population of reproductive
age, defined as abnormally elevated TSH (Thyroid stimulating
Hormone) concentration is 2 to 4%.1,2

There is an alteration in metabolism of the reproductive
steroids, mainly estradiol and testosterone. These cause
inappropriate estrogen feedback and hence result in anovulation.
One of the first signs of sub-clinical hypothyroidism is that
there is a subtle increase in prolactin levels. Treatment with
thyroid replacement normalizes prolactin levels too.

In males, it is the thyroid antibodies which cause disturbances
of the semen with anatomical as well as functional parameters
altered depending on the auto-immune response to the thyroid
antibodies.

Thyroid dysfunction is a common cause of infertility and easily
managed by correcting the inappropriate levels of thyroid
levels. TSH secretion is closely linked with reproductive
function and is known to affect the menstrual cycle. The impact
of hypothyroidism on the menstrual cycle has been known since
1950.3 Severe hypothyroidism is commonly associated with failure
of ovulation, but ovulation and conception can occur in milder
hypothyroidism. This impact on menstrual function and ovulation
is related to numerous interactions of thyroid hormones with the
female reproductive system.

In women attending the infertility OPD, the incidence of Thyroid
dysfunction was twice that of general population. The common
cause was anovulation. These ovulatory disorders included
evidence of galactorrhea, hirsuitism, amenorrhea and
menorrhagia. In a study on Indian women, Joshi et al found 68.2%
of menstrual abnormalities in hypothyroid women (15/22) compared
with 12.2% of healthy controls (6/49).5

Many patients with raised TSH also had a raised prolactin and
this is due to increased production of TRH. This raised
prolactin then causes anovulation through the altered
dopaminergic pathway. The resultant hyperprolactinemia is the
cause of the ovulatory dysfunction and in 1–3% of cases,
especially when associated with galactorrhea.6 An alternative
hypothesis is that diminished synthesis and secretion of
dopamine in the hypothalamus could account for loss of
dopaminergic inhibitory influences on secretion of PRL, TSH and
also to some extent on the LH.7 It has been recommended that in
the presence of raised TSH along with raised PRL levels, the
treatment should be first to correct the hypothyroidism before
evaluating further causes of raised PRL.8 Another study in the
Asian sub-continent also found a higher incidence of raised
serum prolactin and serum TSH level in women with infertility.
It also noted that the Prolactin level was high in more
frequently in patients with primary infertility and TSH level
was higher in patients with secondary infertility.9 Another
presentation of infertility can be decreased sexual desire
(libido) associated lethargy of hypothyroidism.

T3 modulates FSH and LH action on steroid biosynthesis and
multiple T3 binding sites have been identified in mammalian
granulosa and stromal cells and more recently in human oocytes.
Any impairment in locally available T3 may therefore disrupt
normal female reproductive function. 10

How does thyroid influence Ovulatory cycle?

Dysfunction of thyroid secretion results in inappropriate
production of TRH. This interferes with normal physiological
pulsatile GnRH secretion which is required for normal follicular
development and maturation. Hypothyroidism in adult women often
results in changes in cycle length and blood flow. In older
series, menorrhagia (increased blood flow) was the most
prevalent symptom and occurred in 60% of overt hypothyroid
women.4
Hypothyroidism also results in altered peripheral estrogen
metabolism. Decrease in SHBG and its binding activity, together
with an altered peripheral metabolism of estrogen may result in
abnormal feedback at the pituitary level.1 The anovulation or
oligo-ovulation causes a short luteal phase because of delay in
LH response and inadequate corpus luteal progesterone secretion
. In adult women, more common ovulatory disorders including
galactorrhea, hirsuitism, amenorrhea and menorrhagia have been
reported. 4,,6,7,9

In the presence of anovulation, ovarian androgen production
increases with higher biologically active androgens which are
compounded by the low SHBG. These changes further contribute to
anovulation and an increased incidence of hirsuitism. It is
important to remember that independent of hormonal changes,
menorrhagia can result from defects in hemostasis, involving
decreased levels of factors VII, VIII,IX and XI and must also be
evaluated and treated as well.11

DIAGNOSIS:The diagnosis is very easy and consists of
combination of clinical evaluation and serum hormonal assays of
TSH, total or free T3 and T4. In cases of high suspicion, TSH
levels and free T4 are the most important.

Sub-clinical Hypothyroidism:Sub-clinical hypothyroidism is defined as elevated serum TSH
in the presence of free thyroxin (fT4) concentrations within the
normal reference range. After the introduction of
third-generation assays for serum TSH, it is more often
detected. Subclinical hypothyroidism results from the same
causes as overt hypothyroidism and is an important cause of
menstrual dysfunction. Considering the largest cohorts published
the prevalence of sub-clinical hypothyroidism in infertility
ranges from 1 to 4% and most cases are associated with ovarian
dysfunction. However, these studies looking at the association
of sub-clinical hypothyroidism and infertility are poorly
controlled.

Recent data indicate that variations of free T4 in the
individual are narrower than variations within the reference
range for the population. These data may indicate that normal
fT4 (for the population reference range) could reflect an
abnormal fT4 for the individual patient with increased serum
TSH.12
A study recommend performing TRH(thyroid releasing hormone)
stimulation testing in women suffering from ovulation disorders
who have normal basal TSH levels ,followed by repeat assessment
of thyroid function to enable treatment with thyroxin in cases
with abnormal results .13 Treatment with hormone in sub-clinical
hypothyroidism is still debatable, there are two schools of
thoughts one says give hormone only in documented deficiency
while the other believes in thyroxin hormone treatment to
improve the outcome.

Treatment of Hypothyroidism:Hormone therapy with thyroxin extract (Levo thyroxin) is the
choice of treatment in established hypothyroidism. It normalizes
the menstrual cycle, prolactin level and improves the fertility
rate.

THYROID AUTOIMMUNITY AND INFERTILITY

Autoimmune abnormalities have been investigated for
possible associations with reproductive failure. The tests for
thyroid autoimmunity (AITD) include testing for 1. Anti-TPO and
2 Anti-thyroglobulin antibodies

AITD is the most common autoimmune disorder in the female
population, affecting 5–10% of women of childbearing age and
secondly it is the most frequent cause of thyroid failure
including both sub-clinical as well as overt
hyperthyroidism.14,15,16

AITD can also be present without thyroid dysfunction and will be
undiagnosed. In patients with clinical suspicion of thyroid
dysfunction and infertility should have the tests done. Many
cases of unexplained infertility may have the AITD positive. It
was noted that in infertile women thyroid autoimmunity features
are significantly more frequent than in healthy fertile
controls. In patients with unexplained infertility and with
endometriosis subgroup, the Thyroid Peroxidise antibody (TPO-Ab)
tests are positive more frequently than in fertile women.17 In a
Spanish prospective study higher prevalence of thyroid
autoimmunity (Anti TPO antibodies) were found in unexplained
infertility and implantation failure than in the control
group.18

In
severe cases of autoimmune disorders like Graves disease and
Hashimoto’s thyroditis which is caused by proteins and white
cells in the blood can also attach the same proteins in the
ovaries. This leads to shriveling of the ovary, failure to
ovulate and in some cases there is a total ovarian failure
causing, premature menopause and infertility. Treatment options
for thyroid autoimmunity are low dose heparin, aspirin and IV
immunoglobulin.

HYPERTHYROIDISM AND INFERTILITY

The prevalence in the general population is around
1.5%19,20 A suppressed serum TSH and increased FT4, FT3 or both
characterize hyperthyroidism along with the clinical signs and
symptoms as tabled above.

Possible Mechanism for Infertility:The exact impact of hyperthyroidism on fertility remains
ill-defined. Menstrual disturbances in hyperthyroidism have been
described by Von Basedow in 1840 and confirmed by other groups.4
Joshi et al found menstrual irregularities in 64.7% of
hyperthyroid women, compared with 17.2% of healthy controls in a
study in india. The incidence of menstrual abnormalities was
two-and-a-half times higher than in the controls.5

Krassas et al observed irregular cycles in only 46 of 214
hyperthyroid women (21.5%). Twenty-four women had hypomenorrhea,
15 polymenorrhea, 5 oligomenorrhea, 2 hypermenorrhea and none
had amenorrhea. The prevalence of similar abnormalities in the
control population was 8.4%.19 but surprisingly most women with
hyperthyroidism maintain ovulatory function as seen on
follicular studies and the incidence of spontaneous pregnancies.
This has also been confirmed by endometrial biopsies.1

In contrast to the hypothyroid state, SHBG production is
increased. Therefore the estrogen metabolism is altered and
conversion of androgens to estrogens increased. Hyperthyroidism
also augments gonadotropin response to GnRH and baseline
gonadotropin concentrations are frequently elevated. The
decrease in menstrual flow may also relate to effects on
haemostatic factors, including the synthesis of factorVIII.1,20

As for hypothyroidism, most studies on the prevalence of
hyperthyroidism in infertility are derived from uncontrolled,
retrospective cohort studies. An Indian study by Joshi et al
showed that out of 53 hyperthyroid patients, 5.8% had primary
and secondary infertility.5 Usually, treatment corrects cycle
changes observed with hyperthyroidism. The exact impact of
hyperthyroidism on fertility remains ill-defined.

DiagnosisDiagnosis is made with clinical findings and serum TSH, T3,
T4 assays. Low TSH levels with raised T3 and T4, either one or
both clinch the diagnosis. However, to know the cause of
hyperthyroidism, other investigations like ultrasonography,
radioactive iodine uptake and antithyroid antibodies would need
to be carried out.

Treatment:Treatment of overt hyperthyroidism normalizes menstrual
pattern. Data on the impact of treatment of subclinical
hyperthyroidism are not available. The mainstay of treatment is
anti-thyroid drugs. Radio-iodine therapy may be needed in some
cases. And surgery may also be suggested depending on the cause.

ANTITHYROID DRUGSCarbimazole(10-20mg 8hrly), Methimazole(10-15mg 8hrly),
propylthiouracil(100-200mg 8hrly) are the drugs available for
treatment, dosages depend on severity. For symptomatic relief
beta blocker like Propanolol (40-60mg 6-8hrly) can be given.
Propylthiouracil can be used safely in patients undergoing
infertility treatment and continued during pregnancy under
supervision.

Surgery should be considered in the following cases:

1. In presence of large goiter/ multinodular goiter
2. In patients with poor compliance to drugs
3. In patients with persistent side effects with drugs.

Irradiation with I-131(radioactive iodine) can be used to
destroy thyroid gland in certain cases. Krassas et al reviewed
the impact of radioiodine in the management of hyperthyroidism
in patients of reproductive age. It was observed that fertility
is not disturbed in the long term and I131 is not
contra-indicated in hyperthyroid patients because of the risk of
infertility.1

There are some studies which say that women with positive
TPO-Ab before the first ART cycle have significantly increased
risk of miscarriage and there is increased prevalence of thyroid
antibodies in euthyroid women with a history of recurrent in
vitro fertilization failure. Thyroid antibodies might be
independent markers for reproductive failure in IVF-ET programme
but larger studies needed.22,23

Summary

Women presenting with infertility should be screened for
thyroid function. Earlier guidelines mention it is unnecessary
in asymptomatic patients but evidence today is clear that all
patients with infertility should be screened. A retrospective
analysis of the results of routine thyroid function screening
showed that occult thyroid dysfunction was seen in 5.1% of the
population studied. So the assessment of thyroid in infertility
is recommended. A clinical challenge is to identify cases of
sub-clinical hypothyroidism and improve clinical outcomes. There
may be a role of anti-thyroid antibodies in cases of repeated
IVF failures, which needs more studies. The take home message is
to routinely screen for thyroid dysfunction and if present treat
it effectively to improve pregnancy rates.